The objective of this proposal is to analyze how the influenza virus A/PR/8/34 hemagglutinin (PR8 HA) is recognized as a defined self antigen in HA transgenic (HA Tg) mice. HA Tg mice will be immunized or infected with mutant PR8 viruses that contain amino acid substitutions in defined HA T and B cell determinants. The responses that can be induced in HA Tg mice will be compared to the responses that are induced in non-Tg BALB/c mice, and related to the wealth of information describing how the HA is recognized as a foreign antigen. The specificity and genetic basis of T cell tolerance to the HA will be systematically analyzed by comparing the responses of HA Tg and BALB/c mice to analogs of a helper T cell determinant that display varying degrees of cross-reactivity with the PR8 HA. Whether infection of HA Tg mice with mutant viruses containing these analogs can induce T cells that cross-react with the PR8 HA as a defined self antigen will also be examined. The extent of B cell tolerance in HA Tg mice will be assessed by immunization with antigenic variant viruses that contain amino acid substitutions in B cell antigenic sites. Whether tolerance to the PR8 HA focuses the antibody response of HA Tg mice toward epitopes that contain the amino acid substitution will be analyzed. In addition, whether HA Tg mice use the same prominent H and L chains that BALB/c mice use to recognize the HA will be examined. How the pattern of expression of the transgenic HA influences its recognition as a self antigen will also be assessed. Different HA Tg lineages will be compared for the tissue location, the level of expression, and the developmental stage at which the HA is expressed. Whether different patterns of expression lead to distinct manifestations of self tolerance will be examined by analyzing the responsiveness of HA Tg mice from different lineages to immunization or infection with PR8 virus. Together, these analyses will provide unique and fundamental insights into the specificity and genetic basis of tolerance to the HA as a defined self antigen. In addition, 'molecular mimicry' models of autoimmunity, which propose that an immune response to a microbial antigen can induce lymphocytes that cross-react with a self antigen will be directly evaluated.